Mitochondria are essential organelles in plant and animal cells that arise from a prokaryotic ancestor and play a key role in processes such as oxidative phosphorylation, aerobic metabolism of glucose and fat, calcium signaling, and apoptosis (Wallace, Proc. Natl. Acad. Sci. USA 91:8739 (1994) and Dyall et al., Science 304:253 (2004)). The human mitochondrial genome is 16,568 bp and encodes a limited number of mitochondria-specific proteins, rRNAs, and tRNAs (Brandon et al., Nucleic Acids Res. 33:D611 (2005)). All other mitochondrial proteins are encoded in the nucleus. The mitochondrial genome is maternally inherited and undergoes a high rate of mutation because mtDNA is not protected by histones, is inefficiently repaired (Mason et al., Nucleic Acids Res. 31:1052 (2003)), and is exposed to oxygen radicals generated by oxidative phosphorylation (Wallace, Proc. Natl. Acad. Sci. USA 91:8739 (1994)).
A large number of heritable diseases are caused by mutations that are found in mitochondrial and nuclear genes encoding mitochondrial proteins and that produce heritable skeletal or cardiac myopathies (Wallace, Proc. Natl. Acad. Sci. USA 91:8739 (1994), Brandon et al., Nucleic Acids Res. 33:D611 (2005), Wallace, Science 283:1482 (1999), and Green et al., Science 305:626 (2004)). In addition, environmentally-induced mutations in mtDNA have been implicated in many common acquired disorders, including ischemic diseases of the heart and brain, neurodegenerative diseases, some liver diseases, and some cancers (Wallace, Science 283:1482 (1999)). For example, disorders involved in mitochondrial dysfunction affecting cellular processes include but are not limited to neuropsychiatric diseases such as bipolar disorder (BD), depression, schizophrenia, and Rett's syndrome; neurodegenerative disease like Alzheimer's disease, Parkinson's disease, Friedreich's ataxia (and other ataxias); amyotrophic lateral sclerosis (ALS) (and other motor neuron diseases); Huntington's disease; and various neuropathies and myopathies, such as Leber's hereditary optic neuropathy (LHON), encephalopathy, lactacidosis, stroke (MELAS); myoclonic epilepsy with ragged red fibers (MERFF); macular degeneration; epilepsy; and mitochondrial myopathy.
The use of antioxidants targeted to mitochondria, which has been shown to be effective at slowing disease progression, has been reported by Jauslin et al., (FASEB J. 17:1972 (2003)). Therapeutic benefit of administering γ-tocopherol derivatives and metabolites as antioxidants and nitrogen oxide scavengers which treat high blood pressure, thromboembolic diseases, cardiovascular disease, cancer, natriuretic disease, formation of neuropathological lesions and reduced immune system response are disclosed in U.S. Pat. Nos. 6,555,575; 6,242,479; 6,150,402; and 6,410,589. The use of certain chroman derivatives in cosmetic and dermatological preparations is disclosed in U.S. Patent Publication No. 2002/0127252. The beneficial effects of Vitamin E in the progression of a number of major degenerative diseases of the nervous system has been examined in Fryer, Nutritional Neuroscience 1:327 (1998).
Numerous attempts have been made to treat disease associated with mitochondrial dysfunction using transplanted tissues or cells. Attempts to treat such diseases with replacement cells can be complicated by the necessity of replacing diseased tissue rather than improving the function of existing cells and tissue.
The present invention addresses the need for new therapies for conditions characterized by mitochondrial dysfunction without the replacement of existing cells. The invention also features methods of diagnosing neuropsychiatric (e.g., bipolar disorder) and neurodegenerative disorders based on mitochondrial structural abnormalities.